Process of and composition for combating epilepsy



United States Patent Ofice 2,883,392 Patented Apr. 21, 1959 PROCESS OF AND COR [POSITION FOR COMBATING EPILEPSY George Karmas and Robert A. Mallory, Somerville, N.J.,

assignors to Ortho Pharmaceutical Corporation, a corporation of New Jersey No Drawing. Application August 13, 1957 Serial No. 677,834

1 Claim. (Cl. 260-310) This invention relates to l-hydroxymethyl-3-substi tuted-pyrazoles. These novel compounds possess particular value as 'anti-convulsants and are useful in the treatment of epilepsy.

Epilepsy has been defined as a cerebral dysrhythmia which may or may not be accompanied by loss of consciousness and body movements. It is now known that epileptic convulsions are related to the flow of electricity from neurons of the cerebral cortex. The type of chemical reaction which is responsible for these cerebral neuronal discharges is not known, but generally, convulsions and loss of consciousness are characterized by abnormally fast brain waves. When the patient suffers loss of consciousness and convulsions, the seizures are referred to as grand mal, a form of major epilepsy. However, convulsions do not necessarily accompany epilepsy, and in some instances consciousness is not lost. When the patient loses consciousness but convulsions are not observed, the attacks are known as petit mal. A third type of epilepsy has been clinically classified as psychomotor epilepsy.

Many drugs are known which reduce or diminish epileptic seizures in man. In general, those drugs which will act as depressants of nervous transmission are effective for this purpose. The hypnotics, such as the barbiturates, are effective in doses sufficient to produce anesthesia. Phenobarbital is one of the better anti-convulsants, but must be administered in hypnotic doses. The related hydantoins and oxazolidinediones have also been found to possess anti-oonvulsant properties. Such drugs, however, interfere to a greater or lesser extent with the normal activities of the patient.

It is most important, that any drug which is used as an anti-convulsant have very low toxicity since the nature of epilepsy requires that the patient use the drug daily and over a long period of time. The ideal anti-convulsant drug should be a non-toxic, well tolerated, long acting, and devoid of sedative effects.

It is a purpose of this invention to provide a method of reducing or eliminating convulsions in animals and in man by administering anti-convulsant compositions. Our new compositions are useful for veterinary purposes. Effectiveness has been found for a variety of animals, including dogs, mice, rats, and monkeys.

It is a further object of this invention to provide an anti-convulsant composition in unit dosage form which has a high protective index and is non-toxic in use over a long period of time.

Still another object of this invention is to provide l-hydroxymethyl-3-substituted pyrazole compositions for use in the treatment of epilepsy.

The present invention is particularly concerned with the 1-hydroxymethyl-3-alkylpyrazoles having the structure in which R is selected from the group consisting of a1- kyl and alkenyl radicals, R is selected from the group consisting of hydrogen and :alkyl radicals; the total number of carbon atoms in both R and R being not more than eleven and not less than nine. It has been found that the aforesaid pyrazoles have unexpected and unobvious properties of great value in combating epilepsy. These compositions may take the form of tablets, powders, capsules, or other dosage forms which will be particularly useful for oral ingestion. The compositions may take the form of active materials, namely the l-hydroxyme-thyl-3-substituted pyrazoles, admixed with solid diluents and/or tableting adjuvants such :as corn starch, sucrose, lactose, magnesium stearate, talc, aluminum hydroxide, calcium carbonate gums such as acacia, or the like. Any of the tableting materials used in pharmaceutical practice may be employed where there is no incompatibility with the l-hydroxymethyl-3substituted pyrazoles. The material may be placed in a gelatin capsule and administered in that form. Alternatively, the l-hydroxymethyl-3substituted pyrazoles may be emulsified in a liquid in which the 1-11ydroxyrnethy1-3substituted pyrazoles are not soluble.

This invention emphasizes the use of 3-n-unclecylpyrazolel-methanol and 3- (4,8-dimethylnonen-7-yl pyrazolyll-methylol in the treatment of epilepsy.

It has been found that only certain members of the l-hydroxymethyl-3-substituted pyrazole series have great value in combating epilepsy. Insofar as is known, the physiological properties of the 1-hydroxymethyl-3-substituted pyrazoles have not been heretofore investigated; nor have any of these compounds been applied for therapeutic purposes.

Anti-convulsant drugs may be assayed in the laboratory by the minimum electro-sh-ock method. In this procedure, the drug is administered orally to the animals under test. After one hour, the animal is subjected to a direct-current stimulus that is approximately equal to three times the current necessary to produce maximum seizures. The effectiveness of various l-hydroxymethyl- 3-substituted pyrazoles as anti-convulsants is summarized in Table I. In this table, the first column gives the effective dose in milligrams per kilogram required to prevent convulsions in one-half of the animals subjected to the minimum electro-shock procedure. the second column indicates the amount of drug in milligrams per kilogram that produced neurological toxic symptoms in onealf of the experimental group. The third column of this table reports the amount of drug, again in milligrams per kilogram, that was fatal to fifty percent of the test group. Column four indicates the protective index (N.T.S.5o-IED) and the fifth column gives the therapeutic index (LD5OZED5Q) It will be noted that the number of carbon atoms in the hydrocarbon substituents is critical as the protective index of the l-hydroxymethylpyrazole falls off rapidly if the total number of carbon atoms in the substituent is more than eleven or less than nine.

The 1-hydroxymethyl-3-substituted pyrazoles of this invention are prepared by formylation of a ketone and condensation of the formyl ketone with aqueous hydrazine. The following example described the preparation of 3-undecylpyrazole. Other members of this series may be prepared by the same method, substituting a homologous ketone for the methyl undecyl ketone.

Example I S-UNDECYLPYRAZOLE A Suspension of sodium butoxide is prepared by stirring vigorously and refluxing a mixture of 23 g. (1.0 mole) of sodium metal, 100 ml. of butanol and 1600 ml. of toluene until hydrogen evolution has ceased. This is then cooled to 5 C. and is stirred while a solution of 100 ml. of ethyl formate and 225 g. (1.0 mole) of methyl undecyl ketone in 200 ml. of toluene is added in one portion, and then the reaction mixture is stirred at 20 C. for two days. To this is now added 800 ml. of 5% aqueous sodium chloride and 800 ml. of ether and, after stirring briefly, the layers are separated and the aqueous phase is again extracted with 500 ml. of ether. The combined ether solution is extracted with two 500 ml. portions of 2% aqueous sodium hydroxide. All aqueous portions are now combined and 68 ml. of 85% aqueous hydrazine hydrate is added and this mixture is boiled gently under reflux for one hour after the preliminary removal (by distillation) of ether which has been retained by the aqueous solutions.

After it has been cooled to 20 C. the reaction mixture is extracted with two 500 ml. portions of ether which are combined and dried with anhydrous potassium carbonate and then concentrated by distillation. The residual oil is twice distilled under vacuum to give 128 g. (58%) of colorless 3-undecylpyrazole, of boiling point 140-142" C. at 0.1 mm. of pressure.

Example 11 3-N-UNDECYLPY RAZOLYL-l-METHANOL The l-hydroxymethyl derivatives of the 3-substituted pyrazoles are obtained by warming the pyrazoles with an excess of aqueous formaldehyde and a small amount ethanol or methanol. A mixture of 15 grams (0.0676 mole) of 3-undecylpyrazole, 15 ml. (an excess) of 37% aqueous formaldehyde and ml. of ethanol is vigorously shaken and warmed at 40 C. for ten minutes. The reaction mixture is diluted with 100 ml. of water and extracted with two 70 ml. portions of chloroform which are subsequently combined, washed with 100 ml. of water, dried over magnesium sulfate and evaporated to a viscous oily residue. The product is recrystallized from hexane and pentane to give 7.8 g. (46% yield) of white flakes, melting point 5656.5 C. Analysis calculated for CH23N2OZ TheoryC, H, 11.18. F0undC, 71.39; H, 11.35.

Example III 3-N-DECYLPYRAZOLYL-l-METHYLOL A mixture of 15 g. of 3-n-decylpyrazole, 15 ml. of 37% aqueous formaldehyde and 10 ml. of ethanol is vigorously shaken and warmed for 15 minutes at 50 C. The mixture is placed in the refrigerator overnight, and then poured into 100 ml. of water and extracted six times with 10 ml. portions of methylene chloride. The combined extracts are washed with a 50 ml. portion of water. The methylene chloride extract is then dried by filtering through anhydrous magnesium sulfate and this solvent is evaporated under vacuum at C. After evaporation of all methylene chloride, the residue is dissolved in 100 ml. pentane and cooled to 0 C. to obtain a small crop of crystals. By repeated evapor i and 4 crystallization, a total yield of 6.3 g. melting at 43-46 C., may be obtained. The'product is recrystallized from pentane to obtain 3.7 g. of crystals with melting point 4446 C., and analyzing for C H N O: TheoryC, 70.54; H, 10.99. FoundC, 70.64; H, 11.27.

Example IV 3N-DODECYLPYRAZOLYL-l-METHYLOL A mixture of 20 g. 3-n-dodecylpyrazole, 20 ml. of 37% aqueous formaldehyde and 10 ml. of ethanol is warmed together for 15 minutes at 50 C. The mixture solidifies upon cooling to 25 C. By the addition of 15 ml. methylene chloride and 100 ml. of water, the solid is liquified and separates into two layers. The methylene chloride layer is separated and the water layer re-extracted five times with 10 ml. portions of methylene chloride. The combined methylene chloride extracts are then washed with 50 ml. of water and dried by filtration through anhydrous magnesium sulfate. The methylene chloride is removed at room temperature under vacuum and the residue is crystallized from pentane. The recrystallized product melts at 51-53 C. and analyzes for C H N O: Theory-C, 72.13; H, 11.35. Found-C, 71.98; H, 11.47. Yield of the recrystallized product is 11.5 grams.

Example V 3-N-NONYLPYRAZOLYL-l-METHYLOL A mixture of 5 g. 3-n-nonylpyrazole, 6 ml. of 37% aqueous formaldehyde and 7 ml. of methanol is shaken to form a clear solution and placed in the refrigerator. This mixture solidifies in the refrigerator but is liquid at 25 C. After one week the mixture is added to an at room temperature. The oily residue smells strongly of formaldehyde even after repeated blowing with nitrogen. The formaldehyde may be removed by permitting the product to stand exposed to the air for about a month. The solid so obtained may then be recrystallized from pentane at 30 C. to give 4.3 g. of product melting at 47.5-49.5 C.

Example VI 3-METHYL4-N-DECYLPYRAZOLYL-l-METHYLOL Seven grams of sodium is dissolved in 250 ml. of ethanol and 50 g. of trideconone-Z is then added to the solution of sodium ethoxide so obtained. The mixture is cooled to 0 C. and 30 ml. of ethyl formate is added dropwise over a period of one-half hour. The mixture is permitted to stand at room temperature for about 16 hours and the ethanol is then removed under vacuum.

To the residue is added 150 ml. of ice water and 200 cc. of pentane. The pentane layer is separated and discarded. Ice is added to the water layer which is then acidified with about 30 ml. of concentrated hydrochloric acid to liberate the formyl ketone. The formyl ketone is extracted from this cooled aqueous solution with about 200 cc. of ether. The ether extract is washed with water and dried over anhydrous magnesium sulfate. The anhydrous ether extract is then placed in a distillation flask and after removal of the ether, the 3-formyltrideconone- 2 is collected at -110 C. at 0.4 mm.-of pressure. Any l-formyl ketone that may be present does not distill as the l-formyl isomer is destroyed by heat.

The distillate is dissolved in pentane and treated with an excess of saturated copper acetate solution to precipitate the copper salt. This copper salt may be recrystallized from normal heptane to give pale green crystals melting at 99-103 C. The 3-formyltrideconone-2 is liberated from its copper salt by suspending the salt in water, acidifying with hydrochloric acid and extracting with ether. The washed and dried ether extract is again subjected to distillation; the product distilling at 100- 107 C. at 0.4 mm. of pressure. The formyl ketone may be crystallized from pentane to give 11.8 g. of crystals melting at 49-50 C. A mixture of 8.8 g. of the 3-formyltrideconone-2 prepared as described above, 2.7 g. of 85% hydrazine hydrate and 150 ml. of ethanol is refluxed for one and onehalf hours and the 3-methyl-4-n-decylpyrazole so obtained is isolated by distillation. The product boils at 128-130 C. at 0.005 mm. of pressure and has a refractive index: n =1.4798.

A mixture of 3 g. of 3-methyl-4-decylpyrazole, 3 ml. of 37% aqueous formaldehyde and 5 ml. of methanol is heated to 50 C. for 15 minutes. Crystals form if the mixture is cooled to 20 C. These crystals may be filtered and have a melting point of 59-60 C. The filtrate is diluted with Water and extracted with methylene chloride. The crude crystals are added to the methylene chloride extract and the resulting solution is filtered through anhydrous magnesium sulfate. Evaporation of the methylene chloride gives a residue that may be crystallized from pentane. The crystals melt at 61-3 C. Analysis for C H N O (percent N): Theory, 11.10. Found, 11.09.

. Example VII 3- (4,8-DIMETHYLNONEN-7-YL) PYRAZOLYL- l-ME'IHYLOL A mixture of 5 g. of 3-(4,8-dimethylnonen-7-yl)pyrazole, 7 ml. of 37% aqueous formaldehyde and 5 ml. of methanol is warmed at 40 C. for 15 minutes and then cooled to 20 C. The mixture is diluted with 25 ml.

of water and maintained at 0 C. for 24 hours. This solution is then extracted six times with ml. portions of chloroform and the combined extracts Washed with water and dried over anhydrous magnesium sulfate. The chloroform is removed at temperatures below 20 C. to give an oily residue that cannot be crystallized from pentane and hexane at temperatures down to -40 C. The infra-red absorption spectra shows none of the original unchanged pyrazole to be present. The oily residue is analyzed for C H N O: Theory-C, 71.95; H, 10.47. Found-C, 72.49; H, 10.96.

The percentage of 1-hydroxymethyl-3-substituted pyrazoles in the compositions of this invention may be varied. It is necessary that the active ingredient constitute a portion such that suitable dosage will be obtained. Obviously, several dos-age unit forms may be administered at about the same time. Although a percentage less than 0.1% of active ingredient is effective, it is preferred to use not less than 0.1% of active agent. The percentage of active agent may be conveniently 10% or 25% or even 50% since activity increases with the concentration of active material. Tablets containing from about 25 to about 50 mg. of the active 1-hydroxymethyl-3-substituted pyrazole are particularly useful. The following formulations are intended to be illustrative only, and may be varied or modified to a considerable extent without departing from the spirit of the invention. We do not therefore intend to limit the invention to the specific embodiments herein set forth.

Example VIII G. Calcium carbonate 0.500 3-n-undecy1pyrazolyl-l-methylol 0.005 Calcium stearate 0.050

The 3-n-undecylpyrazolyl-l-methylol is adsorbed onto 10% of the calcium carbonate by mixing. The remaining calcium carbonate, previously granulated with water and dried, is added to this pyrazole mixture. The calcium stearate is then added and after mixing until uniform, the mixture is compressed into tablets.

The 3-n-undecylpyrazolyl-l-methylol is adsorbed onto 10% of the aluminum hydroxide with mixing. The remainder of the aluminum hydroxide is then granulated with the sucrose, lactose, and gelatin solution and dried at 50 C. These granules are then mixed with the pyrazole-aluminum hydroxide composition and magnesium stearate until uniform and compressed into tablets.

Exdmple X G. Calcium carbonate 0.250 Lactose 0.250 Acacia solution 0.005 3-(4,8-dimethylnonen-7-yl)pyrazolyl-l-methylol 0.050 Magnesium stearate 0.005

The 3-(4,8-dimethylnonen-7-yl)pyrazolyl-l-methylol is adsorbed onto 10% of the calcium carbonate with mixing. The remainder of the calcium carbonate is granulated with the lactose and acacia solution and dried at 50 C. These granules are then added with the calcium carbonate-pyrazole mixture and mixed until uniform with the magnesium stearate. The resulting product is compressed into tablets.

Example XI G. Magnesium trisilicate 0.300 Lactose 0.200 Sodium alginate solution 0.005 3- (4, 8-dimethylnonen-7-yl -pyrazolyl-lmethylol 0.050

Magnesium stearate The 3-(4,8-dimethylnonen-7-yl)pyrazolyl-l-methylol is adsorbed onto 10% of the magnesium trisilicate by mixing. The remainder of the trisilicate is granulated with the lactose and sodium alginate solution and dried at 50 C. To these granules is added the 3-(4,8-dimethylnonen-7-yl)pyrazolyl-l-methylol adsorbed on magnesium trisilicate and the magnesium stearate. These ingredients are mixed until uniform and compressed into tablets.

Example XII G. Aluminum hydroxide 0.300 Sucrose, powdered 0.100 Lactose, powdered 0.100 3-(4,8-dimethylnonen-7-yl)-pyrazolyl-1- methylol 0.050 Magnesium stearate 0.005

The 3-(4,8-dimethylnonen-7-yl)pyrazolyl-l-methylol is adsorbed onto 10% of the aluminum hydroxide with mixing. The remainder of the aluminum hydroxide, together with the sucrose and lactose, is then added and the composition mixed until uniform. The magnesium stearate is then added with additional mixing and the product is filled into hard gelatin capsules.

What is claimed is:

The compound 3-n-undecylpyrazolyl-1-methanol.

References Cited in the file of this patent Huttel et a1.: Chem. Berichte, vol. 85, pages 820-5 

